Multi-carotenoids compositions and uses therefor

ABSTRACT

A stable nutritional supplement composition for oral administration comprising about 71% by weight, of a tomato extract containing therein at least 2% to 10% by weight of lycopene, 0.25% to 2% by weight of phytoene, and 0.2% to 2% by weight of phytofluene, and about 29% by weight, of a suitable encapsulating matrix. A suitable encapsulating matrix is an edible oil exemplified by soya oil, pumpkin seed oil, grape-seed oil and the like. The tomato extract may additionally comprise one or more of at least one carotene selected from the group comprising β-carotene, γ-carotene, and δ-carotene, a phytosterol, a tocopheral and a phospholipid. The tomato extract may be further processed into oleoresin emulsions, or into beadlets, or into dry powders. Methods for ameliorating the effects of aging-related urinary tract malfunctions in men, comprising orally administrating on a regular basis, an effective amount of the nutritional supplement compositions disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from my Taiwan Patent Application Serial No. 095111722, filed Apr. 3, 2006, currently pending.

TECHNICAL FIELD

This invention relates to compositions comprising a plurality of carotenoid compounds. More particularly, the present invention is directed to nutritional supplement compositions comprising at least lycopene, phytoene and phytofluene, configured for oral administration as a nutritional supplement. The present invention also relates to methods for use of said compositions disclosed herein.

BACKGROUND OF THE INVENTION

Carotenoids are a group of pigments that are characterized by the color including and ranging from yellow to red. Carotenoids are commonly produced by a wide variety of plant materials and most commonly associated with plants such as tomatoes, carrots and peppers.

Lycopene and its precursor phytofluene are caroteniods commonly found in tomatoes and are the predominant sources of the bright red color associated with tomatoes. Phytoene is a precursor to phytofluene, lycopene and other carotenoids, and is also found in high concentrations in tomatoes. Lycopene is generally present in the plasma of the human body; the serum concentrations of lycopene are typically about 2.5 times higher than those of α-carotene and 7.5 times greater than those of β-carotene. Carotenoids are known to have antioxidant properties and consequently, provide numerous beneficial health effects including reducing the potential risks of cardiovascular diseases, cancers, and slowing and/or reversing the degenerative effects of aging on various human physiological activities.

Prostate cancer and benign prostatic hyperplasia (also called BPH) are aging-related conditions that affect prostate gland physiology and impair urinary function in men. As many men age, their prostate glands slowly enlarge causing (a) obstructive symptoms exemplified by weak and/or intermittent urinary streams, a sense of residual urine in the bladder after voiding, and dribbling or leakage at the end of urination, and/or (b) irritative symptoms as exemplified by urgency of micturation, increased frequency of urination, and uracratia. Obstructive and irritative urinary symptoms are commonly referred to as lower urinary tract symptoms (LUTS). The current treatments of prostrate cancer, BPH and LUTS symptoms consist of drug therapies and major surgery. The two primary drug classes used are alpha-blockers and 5-alpha-reductase inhibitors, which should be taken for life in order to get the persistent efficacy. When surgery is considered, the results are usually positive, but there are risks associated with such surgical operations.

SUMMARY OF THE INVENTION

The exemplary embodiments of the present invention, at least in preferred forms, are directed to stable multi-carotenoids compositions useful for oral administration as nutritional supplements, wherein the compositions comprise at least lycopene, phytoene, phytofluene components, and a suitable carrier.

According to one aspect, the lycopene, phytoene, and phytofluene components of the multi-carotenoid compositions of the present invention are preferably naturally occurring and are preferably extracted from tomatoes as pulp. The tomato pulp is suitably processed into oleoresins or beadlet or dry powder materials. The multi-carotenoid compositions of the present invention comprise said oleoresin, or beadlet, or dry powder materials, are suitably encapsulated in soft-gel capsules, or alternatively, in “hard” capsules, or optionally, configured into tablets, or if so desired, into sachet packets, and like.

According to another aspect, the tomato extracts comprising the multi-carotenoids compositions of the present invention may additionally contain therein addition to the lycopene, phytoene, and phytofluene components, one or more of β-carotene, γ-carotene, and δ-carotene, a phytosterol, a tocopheral and a phospholipid. An exemplary formulation of the multi-carotenoids compositions, comprises lycopene, phytoene, phytofluene, and vitamin E components with trace amounts of β-carotene, γ-carotene, and δ-carotene, within a tomato oil matrix encased in a soft gel capsule. The exemplary formulation may additionally comprise an edible oil exemplified by soya oil, pumpkin seed oil, grapeseed oil and the like.

According to another embodiment of the present invention, there are provided methods for regular oral administration of the multi-carotenoids compositions disclosed herein thereby regularly providing an effective amount of lycopene useful for ameliorating the effects of aging-related urinary impairments and malfunctions in men. Such urinary impairments and malfunctions are exemplified by benign prostatic hyperplasia, prostate cancer, lower urinary tract symptoms such as obstructive symptoms and irritative symptoms, and the like.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides stable multi-carotenoids compositions useful for oral administration as nutritional supplements, wherein the compositions comprise at least lycopene, phytoene, phytofluene components contained within an extract produced from tomato fruits. Suitable tomato fruits are produced by non-genetically engineered plants, and preferably contain high concentrations of lycopene. The compositions are preferably encased in a soft gel capsule and may additionally comprise an edible oil exemplified by soya oil, pumpkin seed oil, grapeseed oil and the like.

The lycopene, phytoene and phytofluene components are preferably processed from tomato fruits into extracts. The components may be concentrated by removing water from the extracts thereby producing thickened pulps that contain therein the lycopene, phytoene and phytofluene components, and additionally comprise β-carotene, γ-carotene, δ-carotene, vitamin E, a plurality of phytosterols and phospholipids. The thickened pulps may be further suitably processed into oleoresin-based emulsions. The oleoresins may be encapsulated within soft gel capsules comprising soya oil or alternatively, pumpkin seed oil. The tomato extracts may be optionally formulated into beadlets that may be packaged if so desired in sachet packets, or alternatively, dried and processed into powders that may be optionally encapsulated or alternatively, tabletted.

A suitable multi-carotenoids composition of the present invention is a soft gel capsule configured for oral administration as a nutritional supplement and comprises about: (a) 71% by weight of a tomato extract containing about 2% to 10% by weight of lycopene, 0.25% to 2% by weight of phytoene, 0.2% to 2% by weight of phytofluene, trace amounts of carotene, β-carotene, γ-carotene, δ-carotene, vitamin E, phytosterols and phospholipids, and (b) 29% weight of a suitable encapsulating matrix exemplified by soya oil or pumpkin seed oil. An exemplary multi-carotenoids composition is a soft gel capsule weighing about 350 mg and comprising firstly, about 250 mg of a tomato oleoresin containing: (a) about 15 mg of lycopene, (b) about 1.5 mg of phytoene, (c) 1.25 mg of phytofluene, (d) about 0.5 mg of vitamin E, (e) about 5 mg of β-carotene, (f) about 1.5 mg of a phytosterol, and (g) 25 mg of a phospholipid, and secondly, about 100 mg of soya oil or alternatively, about 100 mg of pumpkin seed oil and the like.

A 12-week clinical study was initiated with a group of 74 males divided into two sub-groups of 37 individuals each, to assess the effects of an exemplary capsule formulation of the multi-carotenoids composition of the present invention. Twelve individuals were subsequently withdrawn from the study, and the remaining 63 subjects were divided into: (a) a first group of 29 subjects who received a daily oral dose of one 350-mg capsule of the exemplary capsule of the present invention thereby providing a daily nutritional supplement of 15 mg of lycopene, and (b) a second group of 32 subjects who received a daily oral dose of two 350-mg capsules of the present invention thereby providing a daily nutritional supplement of 30 mg of lycopene, on selected clinical parameters associated with prostate and urinary system health. The inclusion criteria for the trial were male subjects over 40 years of age with no prior history or indicators of prostate and/or other cancers, the subjects' PSA levels were between 2.5 and 20.0 ng/ml, and their renal and liver functions were within normal ranges. The exclusion criteria were individuals with fluctuating PSA levels, recent medical histories of urinary tract infection, prostatitis, acute urinary retention, individuals with known allergic reactions to carotenoids, individuals taking medications that may alter serum PSA levels as exemplified by 5-α reductase inhibitors, steroids or hormonal agents, and medications for lower urinary tract infections.

The trial followed a general protocol of, first, screening, evaluation and selection of the individuals for participating in the trial. Second, a 2-week washout period was undertaken during which the individuals maintained their normal lifestyle and eating habits while avoiding all lycopene foods such as tomato products, guava, pink grapefruits and the like. Third, at the end of the 2-week washout period, each individual's serum was sampled (i.e., the first sample) after which, they were assigned to one of the two lycopene dosage groups. Fourth, the individuals in each group received their daily dosage for 12 consecutive weeks. Each indvidual's was sampled after one week (i.e., the second sample), after four weeks (i.e., the third sample) and after twelve weeks (i.e., the fourth sample). Each serum sample was assayed to quantitatively determine therein the PSA, lycopene, creatine, bilirubin, alanine amino transferase, hemoglobin, cholesterol, low-density lipoprotein, high-density lipoprotein, and testosterone levels. At each sampling time, the test individuals were also responded to questions regarding their urinary functions taken from the International Prostate Symptom Score (IPSS) index developed and validated by a multidisciplinary measurement committee of the American Urological Association (Fowler et al., 1992, Journal of Urology 148:1549-57).

The time “0” data (i.e., the first sample) are shown in Table 1. Individuals receiving a daily lycopene dose of 15 mg via one capsule daily of the exemplary composition of the present invention showed a 2.6 times increase in their serum lycopene levels, while individuals receiving a daily lycopene dose of 30 mg via two capsules daily showed a 3-fold increase in their serum lycopene levels (Table 2). TABLE 1 Summary of test individual baseline data at the first sample time (0 time)* Lycopene dosage Parameter 15 mg/day 30 mg/day Age (years) 63.4 ± 8.1  63.9 ± 9.7  P = 0.9 Median PSA (ng/mL) 8.8 ± 4.2 7.8 ± 3.8 P = 0.3 Median PSA range (ng/mL)  3.5-18.4  2.7-17.5 IPSS 11.3 ± 5.8  12.3 ± 6.5  P = 0.5 Body mass index 24.6 ± 2.0  24.2 ± 2.9  P = 0.9 Serum total lycopene 297.9 ± 127.3 303.0 ± 162.3 P = 0.9 (ng/mL) Serum creatine (mg/dL) 1.07 ± 0.15 1.14 ± 0.15 P = 0.06 Serum bilirubin (mg/dL) 0.9 ± 0.3 0.9 ± 0.3 P = 0.4 Alanine amino transferase 21.6 ± 7.9  18.5 ± 6.3  P = 0.08 (U/L) Serum hemoglobin (mg/dL) 14.4 ± 1.0  14.6 ± 1.2  P = 0.5 Serum cholesterol (mg/dL) 198.4 ± 33.7  205.9 ± 32.5  P = 0.4 Low-density lipoprotein 122.5 ± 28.2  132.1 ± 54.9  P = 0.4 (mg/dL) High-density lipoprotein 41.5 ± 9.2  44.2 ± 10.3 P = 0.3 (mg/dL) Serum triglycerides 122.6 ± 53.1  115.6 ± 68.4  P = 0.7 (mg/dL) Serum testosterone (mg/dL) 4.5 ± 1.7 4.8 ± 1.9 P = 0.5 *Data are means ± standard deviations

TABLE 2 Changes in serum lycopene levels after 12 weeks of supplementation with the exemplary composition of the present invention*. Lycopene dosage Sample time 15 mg/day 30 mg/day Time “0” (baseline) 279.9 ± 127.3 303.0 ± 162.3 P = 0.9 After 12 weeks 780.0 ± 224.1 947.5 ± 290.4 P = 0.01 *Serum lycopene levels are reported as ng./mL means ± standard deviations.

The median results indicated that the test individuals from both daily dosage groups showed marginal declines in their PSA levels over the 12-week study (Table 3). However, a sub-group of 23 test individuals with baseline PSA levels greater than 8.0 at the first sampling time (i.e., time “0”), from both treatment groups, showed significant decreases in their PSA levels over the 12-week study (Table 4). TABLE 3 Changes in PSA levels during 12 weeks of supplementation with the exemplary composition of the present invention*. Lycopene dosage Sample time 15 mg/day 30 mg/day Time “0” (baseline) 8.8 ± 4.2 7.8 ± 3.7 After 4 weeks 8.3 ± 3.9 7.0 ± 3.8 % change from baseline   −4%   −9% P = 0.08 P = 0.01 After 12 weeks 8.0 ± 3.8 7.5 ± 4.0 % change from baseline −5.2% −3.1% P = 0.17 P = 0.22 *PSA data are reported as ng/mL means ± standard deviations.

TABLE 4 Changes in PSA levels in test individuals with elevated baseline PSAs, during 12 weeks of supplementation with the exemplary composition of the present invention. Sample time PSA level (ng.mL) Time “0” (baseline) 12.4 ± 3.2 After 4 weeks 11.2 ± 4.1 % change from baseline −11% P = 0.01 After 12 weeks 10.9 ± 4.0 % change from baseline −12% P = 0.04

The test individuals from both daily dosage groups showed a progressive decline in their IPSS indices over the 12-week study (Table 5). TABLE 5 Changes in test individuals' IPSS indices during 12 weeks of supplementation with the exemplary composition of the present invention*. Lycopene dosage Sample time 15 mg/day 30 mg/day Time “0” (baseline) 11.3 ± 5.8  12.3 ± 6.5  After 4 weeks 9.5 ± 5.0 9.0 ± 5.0 % change from baseline −14% −24% P = 0.002 P < 0.001 After 12 weeks 9.1 ± 5.9 7.5 ± 4.0 % change from baseline −17% −32% P = 0.012 P < 0.001 *IPSS data are reported as points means ± standard deviations.

Furthermore, the test individuals from both daily dosage groups showed progressive declines in their obstructive IPSS scores and their irritative IPSS scores over the 12-week study (Table 6). TABLE 6 Changes in obstructive and irritative IPSS scores during 12 weeks of supplementation with the exemplary composition of the present invention*. Lycopene dosage Sample time 15 mg/day 30 mg/day Obstructive IPSS Scores* Time “0” (baseline) 5.6 ± 3.7 6.9 ± 4.8 After 4 weeks 4.7 ± 2.9 4.9 ± 3.5 % change from baseline −0.4% −22% P = 0.04  P < 0.001 After 12 weeks 4.7 ± 3.7 4.0 ± 3.7 % change from baseline −3.4% −27% P = 0.18  P < 0.001 Irritative IPSS Scores* Time “0” (baseline) 5.7 ± 3.0 5.4 ± 2.9 After 4 weeks 4.9 ± 2.7 4.1 ± 2.2 % change from baseline  −11% −16% P = 0.009 P < 0.001 After 12 weeks 4.4 ± 2.5 3.6 ± 2.0 % change from baseline  −16% −27% P = 0.001 P < 0.001 *Obstructive and irritative IPSS data are reported as score means ± standard deviations.

The exemplary embodiments of the present invention comprising multi-carotenoids nutritional supplement compositions as disclosed herein for provision of a daily nutritional supplement of at least 15 mg of lycopene, are useful for ameliorating the effects of aging-related impaired urinary functions in men as exemplified by BPH, LUTS, prostrate cancer and the like.

While particular exemplary embodiments of the present invention have been described in the foregoing, it is to be understood that other embodiments are possible within the scope of the present invention and are intended to be included herein. In view of numerous changes and variations that will be apparent to persons skilled in the art, the scope of the present invention is to bc considered limited solely by the appended claims. 

1. A stable nutritional supplement composition for oral administration, said composition comprising: a tomato extract comprising at least 2% to 10% by weight of lycopene, 0.25% to 2% by weight of phytoene, and 0.2% to 2% by weight of phytofluene; an edible oil; and a suitable carrier.
 2. A nutritional supplement composition according to claim 1, wherein the tomato extract additionally comprises at least one carotene selected from the group comprising β-carotene, γ-carotene, and δ-carotene, a phytosterol, a tocopheral and a phospholipid.
 3. A nutritional supplement composition according to claim 1, wherein said edible oil is selected from the group comprising soya oil, pumpkin seed oil, grape-seed oil and the like.
 4. A nutritional supplement composition according to claim 1, wherein said extract is further processed into a formulation component selected from the group comprising oleoresins, beadlets and dry powders.
 5. A nutritional supplement composition according to claim 1, wherein said carrier is selected from the group comprising soft gel capsules, hard capsules, sachet packets, and tablets.
 6. A nutritional supplement composition according to claim 3, wherein said carrier is selected from the group comprising soft gel capsules, hard capsules, sachet packets, and tablets.
 7. A nutritional supplement composition according to claim 1, wherein the tomato extract comprises 4% to 6% by weight of lycopene, 0.4% to 0.6% by weight of phytoene, and 0.3% to 0.5% by weight of phytofluene.
 8. A nutritional supplement composition according to claim 7, wherein the tomato extract additionally comprises at least one carotene selected from the group comprising β-carotene, γ-carotene, and δ-carotene, a phytosterol, a tocopheral and a phospholipid.
 9. A nutritional supplement composition according to claim 8, wherein: the tomato extract comprises 4% to 7% by weight of lycopene, 0.4% to 0.7% by weight of phytoene; 0.3% to 0.6% by weight of phytofluene, 1% to 3% by weight of a tocopherol, 1% to 2% by weight of a β-carotene, 0.3% to 0.6% by weight of a phytosterol, 5% to 10% by weight of a phospholipid; said tomato extract combined with an edible oil; and said combined tomato extract and edible oil is encased within a soft gel capsule.
 10. A nutritional supplement composition according to claim 9, wherein said edible oil is selected from the group comprising soya oil, pumpkin seed oil, grape-seed oil and the like.
 11. A method for ameliorating the effects of aging-related urinary tract malfunctions in men, said urinary tract malfunctions comprising the group of benign prostrate hyperplasia, lower urinary tract symptoms and prostrate cancer, the method comprising orally administrating on a regular basis, an effective amount of the nutritional supplement composition of claim
 1. 12. A method according to claim 11, wherein the regular oral administration of said nutritional supplement composition provides a daily nutritional supplement of at least 15 mg lycopene.
 13. A method for ameliorating the effects of aging-related urinary tract malfunctions in men, said urinary tract malfunctions comprising the group of benign prostrate hyperplasia, lower urinary tract symptoms and prostrate cancer, the method comprising orally administrating on a regular basis, an effective amount of the nutritional supplement composition of claim
 4. 14. A method according to claim 13, wherein the regular oral administration of said nutritional supplement composition provides a daily nutritional supplement of at least 15 mg lycopene.
 15. A method for ameliorating the effects of aging-related urinary tract malfunctions in men, said urinary tract malfunctions comprising the group of benign prostrate hyperplasia, lower urinary tract symptoms and prostrate cancer, the method comprising orally administrating on a regular basis, an effective amount of the nutritional supplement composition of claim
 9. 16. A method according to claim 15, wherein the regular oral administration of said nutritional supplement composition provides a daily nutritional supplement of at least 15 mg lycopene. 